Signaling pathways activated by IIGFs in cancer cells. Although with different affinities, ligands belonging to IIGFs induce IRS-dependent activation of several signaling cascades (RAS/RAF/MEK/ERK, PI3K/AKT/mTOR) leading to gene transcription and protein translation toward stimulatory effects in cancer cells. IGF2-R is structurally unrelated to IGF-1R and IR and is a monomeric receptor serving as scavenger for circulating IGF-2. Abbreviations: AKT, protein kinase B; ERK, extracellular signal–regulated kinase; GDP, guanosine diphosphate GTP, guanosine triphosphate; IGF-1, insulin-like growth factor-1; IGF-2, insulin-like growth factor-2; IGF-1R, insulin-like growth factor-1 receptor; IGF-2R, insulin-like growth factor 2 receptor; INS, insulin; IR-A, insulin receptor isoform A, IR-B, insulin receptor isoform B; IRS, insulin-receptor substrate; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian/mechanistic target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PRAS40, proline-rich AKT substrate of 40 kDa; p70S6k, p70S6 kinase; RAS, rat sarcoma family of proteins; RAF, rapidly accelerated fibrosarcoma protein; Rheb, Ras homolog enriched in brain; TSC, tuberous sclerosis complex; 4EBP1, Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1. All Figures were created using Biorender.com.